The present study includes design and synthesis of new molecular hybrids of 2-methylthiobenzimidazole linked
to various anti-inflammatory pharmacophores through 2-aminothiazole linker, to investigate the effect of such
molecular variation on cyclooxygenase (COX) and 15-lipoxygenase (15-LOX) enzymes inhibition as well as in
vivo anti-inflammatory activity. The chemical structures of new hybrids were confirmed using different spectroscopic
tools and elemental analyses. Benzimidazole-thiazole hybrids linked to acetyl moiety 13, phenyl
thiosemicarbazone 14, 1,3-thiazolines 15a-c and 4-thiazolidinone 16 exhibited significant COX-2 inhibition
(IC50 = 0.045–0.075 μM) with significant COX-2 selectivity indices (SI = 142–294). All hybrids revealed potent
15-LOX inhibitory activity (IC50 = 1.67–6.56 μM). Benzimidazole-thiazole hybrid 15b was the most potent dual
COX-2 (IC50 = 0.045 μM, SI = 294) inhibitor approximate to celecoxib (COX-2; IC50 = 0.045 μM, SI = 327),
with double inhibitory activity versus 15-LOX enzyme (IC50 = 1.67 μM) relative to quercetin (IC50 = 3.34 μM).
Three hybrids (14, 15b & 16) were selected for in vivo screening using carrageenan-induced paw edema method.
Benzimidazole-thiazole hybrid linked to 4-thiazolidinone 16 showed the maximum edema inhibition at both 3 h
and 4 h intervals as well (~119% and 102% relative to indomethacin, respectively). The gastric ulcerogenic
effect of benzimidazole-thiazole hybrid 16 was estimated compared with indomethacin showing superior gastrointestinal
safety profile. In bases of molecular modeling; all new active hybrids were subjected to docking
simulation into active sites of COX-2 and 15-LOX enzymes to study the binding mode of these novel potent dual
COX-2/15-LOX inhibitors.